PROJECT SUMMARY (no more than 30 lines of text): Pancreatic cancer is the fourth-leading cause of cancer death in the U.S. Over 80% of patients present with incurable disease, and the vast majority live for <12 months. The high mortality of pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is largely a consequence of diagnosis at an advanced stage when the tumor is no longer resectable for cure. However, symptoms rarely develop with early disease, and established risk factors for PDAC, such as tobacco smoking, obesity, chronic pancreatitis, diabetes, and family history of PDAC, are insufficient to risk stratify the population for disease screening. Experimental studies indicate that more than a decade elapses from formation of the founder malignant clone to a patient's diagnosis, suggesting a window of opportunity for early detection. Nevertheless, no early detection markers have advanced to clinical use, in part, because little infrastructure has been developed to facilitate rigorous investigation of promising candidates. To address the critical goal of PDAC early detection, we have brought together investigators with a long track-record of collaborative innovation to form the Pancreatic Cancer Circulating Biomarker (Pan-C2-Bio) Consortium. Within this Consortium, we join ongoing patient biospecimen collection at five large cancer centers with four highly promising early detection technologies and sophisticated computer modeling to define a non-invasive PDAC screening strategy. The Consortium will work to achieve three primary goals: (1) generation of a large, unified, thoroughly-annotated human and murine sample bank for testing of early detection markers, (2) definitive evaluation of four highly promising PDAC early detection markers for near-term clinical utility, including circulating cell-free DNA mutations and methylation patterns, cancer-derived exosomes, and metabolism markers, and (3) identification of biomarker-based screening strategies to facilitate early cancer diagnosis in high-risk groups and the general population. Thus, the work proposed by the Pan-C2-Bio Consortium will deliver much-needed biospecimen resources for early detection studies, provide evidence for (or against) the utility of four highly promising PDAC early detection technologies, and demonstrate how new biomarkers can be integrated with previously characterized risk factors to identify individuals for disease screening. With this work, we look to reduce mortality from pancreatic cancer by identifying those at highest risk and diagnosing subclinical disease when curative therapies can be applied.